The long term goal of this research is to develop novel anti-infective disease agents using rational drug design and combinatorial chemistry. The broad objectives of this program are the development of novel antibacterial agents that will address issues of drug resistance. The narrow objectives of the several projects are: discovery of inhibitors of the microbial histidine-aspartate kinase two-component signaling system that is responsible for vancomycin resistance; discovery of inhibitors of a metallopeptidase involved in lipid A biosynthesis; discovery of inhibitors of a 3-arabinosyl transferase involve din the biosynthesis of arabinan segments of mycobacterial cell wall. These molecular targets for antibacterial action come from both gram-negative and gram-positive bacteria. One project will also investigate the total synthesis on sold phase of molecules that exhibit strong anti-infective activity, butt whose molecular targets are not known. Methods to prepare combinatorial libraries of these materials for the discovery of more potent or different antibacterial actions will then be developed. An additional project will involved a "generic" combinatorial library that can be used to map space in active sites of novel protein targets derived from microbial pathogens, allowed integration of combinatorial techniques and rational design principles. One particularly valuable aspect of this work will be the development of a new combinatorial library tagging methodology that permits rapid identification of molecules by NMR. This project will utilize the methods of organic synthesis on the solid phase, combinatorial chemistry, and antibacterial screening. This research will be significant because of the great difficulty medicine now perceives with pathogens that are resistant to conventional antibacterial drugs. Molecules that can modulate signaling events associated with histidine-aspartate kinases would be of great value in both basic scientific investigation and in potential control of microbial physiology and growth. An ancillary benefit of this project will be the development of novel techniques in solid phase synthesis through the total synthesis of natural products.